PROJECT SUMMARY/ABSTRACT A major goal of the UC Irvine MODEL-AD project is to generate data and characterize models of late onset AD. Consistent with this goal, we propose to extend our miniscope imaging technology for functional phenotyping of AD mouse models, and leverage this new imaging approach to examine hippocampal circuit mechanisms that contribute to AD-related memory impairments. Dr. Xu's laboratory at UC Irvine recently has improved miniature microscope (?miniscope?) systems for live brain imaging. The head-mounted miniscope instrument enables our team to examine hundreds of brain cells in action at single cell resolution, as the animal explores freely in environments, and at multiple ages in the same animal. For the proposed study, we will examine spatial correlates of neural activity for single CA1 excitatory neurons in control and AD mice during open-field exploration, and track-based route-running behaviors. The imaging results will reveal maladaptive changes in place cell remapping, place field stability and size in AD mice, which will help to understand whether neurodegeneration in AD mice reduces spatially-specific mapping activity in hippocampal CA1. We will also use the object location memory (OLM) task which involves object-exploration based spatial learning. We will test whether and how control and AD neural activity differ in OLM encoding and retrieval, by imaging ensemble neural activation associated with object exploration across baseline exploration, OLM training and testing sessions. We predict that AD pathology evokes abnormal neuronal ensemble activities leading to impaired behavioral performance that relies on hippocampal circuits. If this approach is validated and proves its significant merit, this will be used to enhance functional phenotyping of mouse models for the MODEL-AD Consortium. This will help to advance our understanding of specific neural mechanisms underlying AD/ADRD etiology in humans.